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Clinical Research
Center
Imaging
Advances in imaging analysis.
A. Grading system development
Coffey et al. (1990), in
collaboration with the Department of Neuropathology at Duke, have
utilized post-mortem MR imaging to characterize white matter
abnormalities. The study was conducted in 17 hypertensive and five
normotensive subjects. Large confluent periventricular hyperintense
signal regions on T2-weighted images were found to correlate with white
matter pallor, gliosis or edema. In other areas, especially deep gray
matter, focal cystic lacunar infarcts also corresponded to rounded or
ellipsoid areas of hyperintense signal (Alston et al., 1989). Small
rounded white matter lesions usually seen in the centrum semiovale were
difficult to identify on post-mortem images. This study combined with
previous autopsy work has led to a pathologically based MRI grading
system (Boyko criteria, [Alston et al., 1989; Boyko et al., 1994]). The
clinical utility of post-mortem imaging in neuropathology has been
recently reported by Boyko and Alston (1994) in a series of 230 formalin-fixed
brains that were scanned. This system has now been utilized in a series
of imaging studies (see below).
B. MRI Morphometry: Development
of Methodology
We have conducted a series of
studies examining the importance of image acquisition protocols and
image analysis methods. For more details see Byrum etal Psychiatry Res
1996 Oct 7; 67 (3):215-34
Methods of measuring brain regions
from MR images include both manual and semi-automated methods. Despite
the development of numerous volumetric methods, there have been only
limited attempts so far to evaluate the accuracy and reproducibility of
these methods. We used phantoms to assess the accuracy of the
segmentation process. Our results with simple and complex phantoms
indicate an error of 3-5% using either manual or semi-automated
techniques. We subsequently used manual and semi-automated volumetric
methodologies to study human brain structures in vivo in five normal
subjects. Supervised segmentation is a semi-automated method that
accomplishes the division of MR images into several tissue types based
on differences in signal intensity. This technique requires the operator
to manually identify points on the MR images that characterize each
tissue type, a process known as seeding. However, the use of supervised
segmentation to assess the volumes of gray and white matter is subject
to pitfalls. In homogeneities of the radio frequency or magnetic fields
can result in misclassification of tissue points during the tissue
seeding process, limiting the accuracy and reliability of the
segmentation process. We used a structured seeding protocol that allowed
for field in homogeneity that produced reduced variation in measured
tissue volumes. We used repeated segmentations to assess intra- and
inter-rater reliability, and were able to measure small and large
regions of interest with a small degree of variation. In addition, we
demonstrated that measurements are reproducible with repeat MR
acquisitions, with minimal interscan variability.
Scan parameters evaluation.
The parameter studies are
summarized in the table below, which shows all relevant scan parameters
including total scan time and volume, as well as voxel volume. Extracted
contrast-to-noise ratios (CNR) were used to evaluate the merit of each
technique. The figure of merit (FOM) quoted combines CNR, scan time and
voxel volume. In the case of dual-contrast studies, the product of the
individual FOM’s is used for comparison with single-contrast studies.
This approach is based on the hypothesis that each stage of contrast
provides an additional degree of freedom and improves the segmentation
capacity. The techniques with the best FOM are the 2 mm SPGR and 2 mm
FSE techniques.
Table: Summary of Technique Pilot
Study
Technique
TR/TE
Matrix Slice/FOV
NEX Scan
Time Voxel Size
SPGR
24/9
256*256 2/200
1
394
1.22
FSE
4000/17/85 256*256
5/200
1
1027
3.05
FSE
4000/17/85 256*256
2/200
1
1027
1.22
VEMP
2500/30/80 256*192
5/200
0.8 780
4.07
T1SE
500/20
256*192 5/200
0.8
234
4.07
Technique
CGM WM
THAL CGM-WM
WM THAL
SIG SIG
SIG
NOISE
CNR
CNR
FOM
SPGR
31
58
44
3.59
7.33
3.90
123
FSE
639 493
590
14.04
10.40
6.91
38
FSE
719 570
705
29.15
5.12
4.65
129
VEMP
640 512
616
12.20
10.50
8.53
55
T1SE
236 302
269
12.95
5.10
2.55
14
We have published our analyses of
these techniques (MacFall et al., 1994; Byrum et al., 1996).
2.
Neuroimaging correlates of normal aging.
Studies
of lesions in normal aging
Our initial published studies have
utilized lesion number, lesion size and severity of white matter disease
by grading (Figiel et al., 1991a). We then used the pathological grading
system to assess the nature of lesions in normal volunteers (Krishnan,
unpublished data). Fifty-five normal volunteers recruited from the
community were studied. Grade 4 DWM was seen in 10% of subjects above
the age of 45. Grade 2 SCH was seen in 5% of subjects above 45 years.
None of the subjects below the age of 45 had any lesions. Confluent PVH
Grade 3 or 4 was seen in 16% of subjects over 45 years. None of the
subjects below the age of 45 had any changes. There was a significant
correlation between age and the occurrence of these changes. Most of the
changes were seen only in the oldest subjects.
Morphometric
Changes in Aging
Using intermediate-T2-weighted
magnetic resonance images, we have demonstrated a marked age-associated
decline in caudate nuclei volume ® = -0.69, p < 0.0001) (Krishnan et
al., 1990) and putamen volume ® = -0.74, p < 0.0001) (McDonald et
al., 1991). Older subjects (>50 years) had significantly smaller
caudate nuclei volume than younger subjects (t = 5.4, df = 37, p <
0.0001) by a two-tailed test. In these 36 subjects, a significant
correlation was also found between caudate volume and putamen volume in
individual subjects ® = 0.60, p < 0.0001).
We also studied cerebellar volumes
(Escalona et al., 1991). Female subjects (n = 21) had significantly
smaller cerebellar volumes compared to males (n = 16) of similar age (t
= 3.9, p < 0.0008, two-tailed test). The correlation between
cerebellar volume and age ® = -0.27) was not statistically significant.
The mean absolute cerebellar volume in this study was 112± 16 cm3
for all subjects, 104 ± 10 cm3 for females and 122 ± 16 cm3
for males.
We have also used midline sagittal
MR images in 36 volunteers to evaluate the effects of age on the
cross-sectional areas of the posterior fossa structures, namely,
cerebellar vermis, midbrain, pons, medulla, and fourth ventricle (Shah
et al., 1991). Our results demonstrate a highly significant age-related
decline in the cross-sectional area of the midbrain ® = -0.44, p = <
0.007), a less prominent decline in the area of the anterior cerebellar
vermis ® = -0.33, p < 0.05) and striking intercorrelations between
the dimensions of the pons, medulla and cerebellar vermis. The
dimensions of the pons, posterior cerebellar vermis, fourth ventricle,
and medulla did not change significantly with age. There were no
significant gender differences in any of the structures studied except
for the midbrain, where male subjects showed more prominent atrophy with
aging than female subjects. For all subjects, the mean (and SD) in cm2
of the measured cross-sectional areas were as follows: anterior
cerebellar vermis = 4.83 (0.6), posterior cerebellar vermis = 6.72
(1.5), total cerebellar vermis = 11.6 (2.0), fourth ventricle = 1.14
(0.5), midbrain = 1.52 (0.4), pons = 5.78 (0.8), medulla = 3.5 (0.6).
The ratio of the anterior vermis to the posterior vermis was 0.74 (0.1).
Cerebral volume (excluding CSF), as estimated by systematic stereology,
also declined with age ® = -0.47, p < 0.004) (Shah et al, 1991).
Midbrain volume was also reduced with age (Doraiswamy et al., 1992).
3.
Neuroimaging in geriatric depression.
Duke investigators have played a
primary role in elucidating many of the structural changes seen in
geriatric depression. These include studies of leukoencephalopathy, gray
matter signal changes and volumetric changes in the basal ganglia. We
describe each of these types of studies below. Additionally, we have
written reviews using our data to support a vascular subtype of
depression (Krishnan and McDonald, 1995; Krishnan and Gadde, 1996;
Steffens and Krishnan, 1998), and we have reported clinical correlates
of this late-onset depression (Krishnan et al., 1995).
Leukoencephalopathy and
Depression:
In our first study of 35 depressed
patients(Krishnan etal 1988) (72% of LOD subjects had leukoaraiosis. The
prevalence was 85% between the ages of 59 and 66, and 100% after age 74.
In a subsequent study, Coffey et
al. (1989) expanded their MRI sample to 51, and they confirmed many of
the same findings. They also compared these subjects to a group of 22
age- and sex-matched elderly volunteers recruited from the community.
Moderate and severe PVH were more common in depressives (62%) than
controls (23%). Large and confluent deep white matter hyperintensities
also were more common in depression (55% vs 14%). Lesions of the basal
ganglia were present in 51% of depressed patients and 5% of controls.
These lesions were associated with risk factors for cerebrovascular
disease. Lesions of the deep gray nuclei and large PVH or DWMH were seen
less frequently in control subjects, suggesting that although vascular
factors may play a role in the aetiology of these lesions, the site
and size of the lesions may be the factors which are important in
rendering an individual vulnerable to depression.
Coffey et al. (1990) replicated
these findings in 67 elderly depressed patients referred for ETC. Many
of the patients were at high risk for cerebrovascular disease (50% were
hypertensive; others had a history of ischemic heart disease or diabetes
mellitus). The leukoaraiosis was associated with late onset (>60
years) of depression.
In addition, Figiel et al. (1991b)
studied the Late onset depressed(LOD) and similar age early onset
depressed (EOD)patients. Results showed a higher occurrence of large
deep white matter lesions and basal ganglia lesions in LOD patients
compared to EOD patients.
Bentley et al. (unpublished data)
studied 115 patients, aged 45 and older, with unipolar major depression,
46 with early-onset depression and 69 with late-onset depression. For
Fazekas ratings, age-adjusted Cochran-Mantel-Haenszel analyses revealed
a significant effect of onset at p < 0.0001 for
periventricular and deep white-matter hyperintensities and at p
< 0.005 for subcortical gray-matter hyperintensities. Cochran-Mantel-Haenszel
analyses of Boyko ratings were significant for onset at p <
0.005 for all measures, with the exception of frontal caps (p
< 0.07). Results of general linear models analyses of covariance for
number and size ratings revealed significantly more hyperintensities in
the left-middle region of the brain (p < 0.05) for late-onset
depressed patients. Marginal significance was observed for lesion size
in the left-middle region (p < 0.07). No significant findings
were noted for anterior and posterior regions or for basal-ganglia
structures. These results are consistent with recent research supporting
the association between late onset of depression and left-sided lesions
(Greenwald et al., 1998; Steffens et al., in press).
Gray matter lesions and
geriatric depression:
Figiel et al. (1990a) found an
association between presence of basal ganglia lesions and other
structural abnormalities and development of interictal delirium in
ECT-treated patients. These findings are consistent with several lines
of data that have implicated subcortical structures in the development
of delirium from other causes, and they suggest that structural changes
in these areas may predispose individuals to develop an interictal
delirium during a course of ECT (e.g., Figiel et al. 1990b).
Coffey et al. (1988) studied 67
elderly depressed patients referred for ETC. Subcortical gray matter
abnormalities were observed in many of the patients with
leukoencephalopathy. Twenty-three of the 31 patients had lacunae in the
basal ganglia, thalamus or pons. Fifteen patients had basal ganglia
lesions. Thalamic lesions were seen in 8 patients.
In another study (Figiel, et al.,
1991c), seven elderly depressed patients (aged 60-86 yrs) with
neuroleptic-induced parkinsonism and 7 age-matched healthy controls
underwent brain magnetic resonance imaging (MRI). All 7 patients had
caudate hyperintensities observed on their brain MRI scans. In contrast,
caudate hyperintensities were not observed in any of the controls.
Findings suggest that the increased incidence of drug-induced
parkinsonian signs in some elderly depressed patients may be at least
partly explained by corresponding structural changes in the basal
ganglia.
Volumetric changes in geriatric
depression:
The basal ganglia are
recognized as putative mediators of certain cognitive and behavioral
symptoms of major depression. Moreover, patients with basal ganglia
lesions have repeatedly exhibited significant affective symptomatology,
including apathy, depressive mood, and psychosis. Using high resolution,
axial T-2 intermediate magnetic resonance images and a systematic
sampling stereologic method, Husain et al. (1991) assessed putamen
nuclei volumes in 41 patients with major depression and 44 healthy
volunteer controls of similar age. Depressed patients had significantly
smaller putamen nuclei compared with controls. Age was negatively
correlated with putamen size in both groups.
Krishnan et al. (1992) also used
magnetic resonance imaging (MRI) to measure the caudate nuclei (CN)
volume in 50 patients with affective disorders during a major depressive
episode and 50 age-matched normal controls. There was a marked decrease
in CN volume in depressed Ss compared with controls and a strong
relationship between age and CN volumes in both groups.
Krishnan et al. (1991a) examined pituitary
gland size in 19 patients with major depression relative to age- and
sex-matched controls. Depressed patients had significantly greater
pituitary cross-sectional area (P = 0.0009) and volume (P = 0.007) than
the controls. This difference was particularly prominent in elderly
depressed patients compared to elderly controls. These results provided
the first demonstration of structural alterations in the pituitary gland
in major depression.
Krishnan et al., (1991b) used a
quantitative MRI to examine the hippocampus in 29 non-depressed
volunteers (aged 26-79 yrs) and in 20 patients (aged 23-80 yrs) with
major depression. Results revealed significantly shortened T1 relaxation
times for the hippocampus in depressed patients. These differences were
particularly prominent in elderly depressed patients. Their findings
pointed to a role for the hippocampus in the regulation of mood and in
the pathophysiology of the stress response, and suggest that major
depression may be associated with biophysical tissue changes in the
aging hippocampus. Axelson etal (1992) showed no change in hippocampal
volume in depressed patients compared to controls . Although interesting
relationship to age of onset was observed.
A study by Parashos et al. (1999),
has supported Krishnan’s (1992) model regarding the neuroanatomical
substrates of depression. Parashos et al. reported MRI volumetric
measurements of the caudate, putamen, thalamus, frontal lobes, orbital
frontal cortex, cerebellum, corpus callosum, and ventricular system in a
group of depressed patients compared with age- and sex-matched controls.
Results revealed significantly smaller volumes of both the caudate and
putamen in depressed patients compared to controls, but not for the
thalamus. Volumes of the frontal lobes were marginally smaller for
depressed patients in the matched subsample and significantly smaller
for an unmatched sample. There was no significant difference between
patients and controls in corpus-callosum volume. In addition, caudate
volume was positively correlated with cognitive status as measured by
the Mini-Mental State Examination (MMSE).
Status of Preclinical Efforts.
Reduced Inhibitory Effect of
Imipramine on Radiolabeled Serotonin Uptake into Platelets in Geriatric
Depression20.
This study represented our initial findings of unique distinctions in
the function of tricyclic antidepressants in geriatric depression as
compared to earlier-onset depression. Using platelets, we found that
elderly depressives exhibited reduced efficacy of imipramine in
inhibiting 5HT uptake, effects that were not shared by aging alone, or
by depression in younger cohorts. This finding provided a basic
biological mechanism for the reduced effectiveness of pharmacotherapy in
geriatric depression and served as the driving force for translating
clinical findings into animal models of geriatric depression.
Do Glucocorticoids Contribute to
the Abnormalities in Serotonin Transporter Expression and Function Seen
in Depression? An Animal Model50. This study developed the
models of chronic minipump glucocorticoid administration to be used in
the current proposal. Indices of HPA axis suppression and CNS and
platelet 5-HT transporter and function were studied; the results
suggested homologies between glucocorticoid excess and changes in
transporter function that were relevant to the issues of HPA axis
abnormalities seen in human depression, and most especially in geriatric
depression.
Serotonin Transporter Expression
in Rat Brain Regions and Blood Platelets: Aging and Glucocorticoid
Effects19.
This study extended the glucocorticoid infusion model to aged rats,
again concentrating on HPA axis regulation and the relationship to 5HT
transporter expression/function. The results indicated that there are
basic biological differences in the effects of glucocorticoids in aged
brain, characterized by reduced transporter expression, effects that
could contribute to effectiveness of antidepressants in geriatric
depression. In a subsequent study (Expression of mRNA Coding for the
Serotonin Transporter in Aged vs. Young Rat Brain: Differential Effects
of Glucocorticoids31), we were able to
demonstrate that the unique regulatory changes in transporter expression
seen after glucocorticoid administration to aged rats involved both
transcriptional and post-transcriptional regulatory mechanisms.
Aging and Glucocorticoids: Effects
on Cell Signaling Mediated Through Adenylyl Cyclase32. This study used the rat
model of aging/glucocorticoid treatment to explore how changes in
postsynaptic reactivity of noradrenergic and serotonergic systems could
contribute to basic biological differences in geriatric depression and
to differences in antidepressant effect. We found that cell signaling
responds differently to glucocorticoids in aged vs. young brain,
effects that would readily influence drugs targeting monoaminergic
function, such as antidepressants. We then showed that there were
prominent regional differences in glucocorticoid effects within the aged
brain (Glucocorticoid-Targeting of the Adenylyl Cyclase Signaling
Pathway in the Cerebellum of Young vs. Aged Rats33) that had a significant impact on the linkage of adrenergic receptors to
cellular function. These distinctions provide an underpinning for the
regional investigations to be undertaken in the current proposal.
Dexamethasone Suppression Test
Identifies a Subset of Elderly Depressed Patients with Reduced Platelet
Serotonin Transport and Resistance to Imipramine Inhibition of Transport21.
Our findings of unique
effects of glucocorticoids on monoaminergic function in the aged rat
model suggested that we should re-examine human populations to see if
resistance to tricyclic antidepressant actions was related to HPA axis
regulation/dysregulation in geriatric depression. Consistent with the
predictions from the animal model, we used the DST to identify a
specific subset of elderly depressives with reduced antidepressant
effect. Importantly for our proposed studies, factors tending to elevate
basal glucocorticoid levels, namely DST nonsuppression, provided
"protection" against the loss of the platelet 5HT transporter
response characteristic of geriatric depression. Subsequently, DST
nonsuppression was used to predict which geriatric patients would
respond successfully to antidepressants22.
Modeling Geriatric Depression in
Animals: Biochemical and Behavioral Effects of Olfactory Bulbectomy in
Young versus Aged Rats1.
As a preliminary study for the current proposal, we conducted work on
the OBX model in young and aged rats to demonstrate both the feasibility
of this approach as well as the differences in effects in young and aged
brain. We found major, age-dependent differences in both the behavioral
and neurochemical effects of OBX. Young OBX rats showed locomotor
hyperactivity and a loss of passive avoidance and tactile startle
responses. In the aged cohort, OBX did not alter avoidance or startle
but produced a much greater effect on locomotor activity and produced
effects that were not seen in young OBX (anhedonia, decreased grooming).
The aged animals also showed atrophy of cortical and midbrain areas
receiving sensory input from the olfactory bulbs, effects that were not
seen in the young animals. The effects on monoaminergic systems (5HT
transporter expression and function, adenylyl cyclase cell signaling)
were completely different in the aged OBX group as compared to young
OBX, with effects often in the opposite direction.
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